Is there a Distinct Phenotype to Memory Loss in Alzheimer's Disease?

Transcription

1 Is there a Distinct Phenotype to Memory Loss in Alzheimer's Disease? David A. Wolk, M.D. Assistant Director Penn Memory Center Assistant Professor of Neurology University of Pennsylvania

2 5 Million

3 Clinical and Pathological Course of AD Clinical State Normal Pre-Clinical AD Cognitive No No Symptoms State Symptoms? Pathologic State No Disease Plaques Early Changes MCI Mild Symptoms y p Mild-ModMod Changes AD Mild-Severe Symptoms y p Mod-Severe Changes Tangles

4 Aging Versus AD

5 Age Associated Cognitive Impairment Park and Reuter Lorenz, Ann Rev. Psychol., 2009

6 Aging Versus Preclinical/Prodromal AD Quantitative differences E.g. Face name memory test Specificity dependent of degree of age related and AD related change Qualitative differences?

7 Topographic p Selectivity of AD Mesulam, 1990

8 Braak & Braak. Acta Neuropath, 1991

9 Doctor Who

10 Downton Abbey Sir Richard Carlisle (Ian Glenn)

11 Dual Process Models of Recognition Memory Two distinct memory processes Familiarity (item memory) Acontextual sense of prior encounter Quantitative Relatively automatic process Recollection (associative, relational) Detailed retrieval, including spatial and temporal context mental time travel Qualitative Controlled Process

12 Proposed Spatial and Temporal Dissociation of Recollection and Familiarity it Neuroanatomy Recollection: Hippocampus, Frontal control networks Familiarity: Perirhinal cortex/lateral entorhinal area Timing Recollection: Slower Familiarity: Faster

13 Binding of Items and Context Model Eichenbaum et al., Ann Rev Neurosci, 2007

14 What Drives Memory Loss with Normal Aging? Buckner, Neuron, 2004 Small et al., Nature Neuroscience, 2012

15 Is Familiarity Selectively Impaired in MCI (prodromal lad)? Normal aging: g recollection impaired, familiarity intact MCI: Predict familiarity (and recollection) should be impaired Alternative: If familiarity and recollection on strength continuum, expect relative sparing of familiarity

16 16 MCI; 21 Controls Three process estimation paradigms Wolk et al., Neuropsychologia, 2008

17 Process-Dissociation Paradigms Intact OLD Rearranged NEW Novel NEW pr = p( Old Intact) p( Old Rearranged) pf = p( Old Rearranged)/(1 pr)

18 Wolk et al., Neuropsychologia, 2008

19 Recollection and Familiarity Impaired in MCI (NC: n=81; MCI: n=65) Recollection Familiarity p< p< Control-Referenced z-scores p<0.001 Wolk et al., Neuropsychologia, 2013

20 Is Familiarity Spared in Normal Aging? (YC: n=18; OC: n=81) Recollection p < Familiarity Wolk et al., Neuropsychologia, 2013

21 Petersen Criteria for MCI (now referred dto as amnestic MCI) Memory complaint (preferably corroborated by informant) Episodic Memory impairment for age and education Largely intact general cognitive function Essentially preserved activities of daily living Do not meet criteria for dementia

22 Amnestic MCI Enriched in patients with AD pathology Specialty Clinics 10 to 15% Conversion to clinical AD per year 1 3% in cognitively normal adults 50 80% over 5 years Community Studies (PAQUID, MoVIES) Lower conversion rate (4 to 8%/year) Reversion to normal (10 to 40% over 2 years)

23 Amyloid Imaging 55-65% PiB positive in most studies of MCI Wolk and Klunk, 2009

24 Does Familiarity Discriminates MCI Based on Amyloid Status (n=22)? Recollection Familiarity p<0.05

25 Limited Neuropsychological py Data Familiarity Recollection Rugg and Yonelinas, TICS, 2002 Bowles et al., PNAS, 2007 Guedj et al., Neuropsychologia, 2010

26 Relationship to MTL Volumes Examined relationship of recollection and familiarity estimates with structure Hippocampus Extrahippocampal MTL (PRC, ERC, PHG) Automated Labeling Pathway (Wu et al., 2006; Andreescu et al., 2007) Wolk et al., Hippocampus, 2011

27 * * Wolk et al., Hippocampus, 2011

28 Correlates of Memory in AD Patients from ADNI ADNI participants with clinical AD diagnosis Mean MMSE: 23.3 ±2.0 (SD) MRI of sufficient quality (n=146) MRI analysis Disease specific ROI s (hippocampus, PRC/ERC) Correlate with standard memory measures differentially dependent on recollection/familiarity

29 Memory Measure Rey Auditory Verbal Learning Test (AVLT) 15 words 5 Immediate memory (learning) trials List B immediate memory 5 minute delayed recall 30 minute delayed recall Recognition memory test

30 AD Cohort from ADNI (n=146) AVLT Delayed Memory Measures Recollection Recall ** ** Familiarity Recollection Recognition * Wolk & Dickerson, NeuroImage, 2011

31 Pure Familiarity Recognition discrimination controlled for free recall Wolk and Dickerson, NeuroImage, 2011

32 Interim Summary Familiarity-based memory is spared as part of normal age-associated cognitive decline Familiarity is dependent on integrity of perirhinal cortex (ERC?) Consistent with early involvement of PRC in AD pathologic process, familiarity-based memory appears sensitive and specific to prodromal AD Is familiarity-based memory sensitive to preclinical AD?

33 Preclinical Alzheimer s Disease 25-30% of CN adults with AD molecular biomarker profile Consistent t with autopsy data Morris et al., Annals of Neurology, 2010

34 Cortical Signature of AD Dickerson et al., Cerebral Cortex, 2011

35 Abnormal Amyloid (PiB) Function Psychometrics Biomar rker Magnit tude Normal Normal Presymptomatic MCI Dementia Clinical disease stage Modified from Jack et al., 2010

36 Abnormal Amyloid (PiB) Function Biomar rker Magnit tude Psychometrics Brain Structure (MRI) Normal Normal Presymptomatic MCI Dementia Clinical disease stage Modified from Jack et al., 2010

37 Abnormal Amyloid (PiB) Function Biomar rker Magnit tude Psychometrics Brain Structure (MRI) Brain Physiology (PET) Normal Normal Presymptomatic MCI Dementia Clinical disease stage Modified from Jack et al., 2010

38 Does Evidence of AD Specific Atrophy Predict tdecline in CN Adults ADNI healthy controls with adequate 1.5 T MRI (n=159) Mean AD signature measure converted to z score > 1 SD bl below mean ADsig hi thin (high h risk ik group) Within 1 SD of mean ADsig Average > 1 SD above mean ADsig thick (lowest risk group) 3 year follow up a priori cutoffs of functional (> 1.0 increase in CDR Sum of Boxes) and cognitive decline (> 1 SD decline)

39 Cortical Thinning in Signature of AD regions predicts decline and CSF AD profile in Cognitively Normal Adults Dickerson and Wolk, Neurology, 2012

40 Relationship of AD Cortical Signature with Recollection/Familiarity β=.55, p< β=.37, p< 0.05 Wolk et al., Neuropsychologia, 2013

41 Summary Biomarkers of neurodegeneration may be valuable in temporal prediction in preclinical phases beyond amyloid status Preclinical disease may be associated with subtle cognitive change Familiarity as possible screening measure? Familiarity as cognitive outcome measure in preclinical trials

42 Collaborators Penn Paul Yushkevich Sandy Das MGH/Harvard Pitt Brad Dickerson John Detre Steve Arnold Steve DeKosky Lauren Mancuso Howard Aizenstein Dasha Kliot Eric Signoff Kti Katie Manning Kathryn Dunfee Funding: K23AG028018; R01AG040271; P30AG010124; Alzheimer s Association